The present invention relates to methods and compositions for treating various forms of pain in mammals. Although the present invention is expected to be useful for virtually all pain types, it is most potent for pain involving hypersensitivity of the nociceptive pathway such as inflammatory pain, persistent chemical pain, and neuropathic pain. At higher doses, the present invention is also effective in acute pain states such as that induced by chemical irritation, gastrointestinal disturbance, migraine and all forms of headache.
Inflammatory pain can occur when tissue is damaged, as can result from surgery or due to an adverse physical, chemical or thermal event or to infection by a biologic agent. Although inflammatory pain is generally reversible and subsides when the injured tissue has been repaired or the pain inducing stimulus removed, present methods for treating inflammatory pain have many drawbacks and deficiencies. Thus, the typical oral, parenteral or topical administration of an analgesic drug to treat the symptoms of pain or of, for example, an antibiotic to treat inflammatory pain causation factors can result in widespread systemic distribution of the drug and undesirable side effects. Additionally, current therapy for inflammatory pain suffers from short drug efficacy durations which necessitate frequent drug re-administration with possible resulting drug resistance, antibody development and/or drug dependence and addiction, all of which are unsatisfactory. Furthermore, frequent drug administration increases the expense of the regimen to the patient and can require the patient to remember to adhere to a dosing schedule.
Chemically induced pain may occur when a patient is exposed to chemical agents that trigger pain response. Commonly, chemical pain is used to test anesthetic or analgesic efficacy of treatment methods.
Some examples of neuropathic pain are diabetic neuropathy, post-herpetic neuralgia (shingles), trigeminal neuralgia, pain associated with AIDS infection and treatment, whip-lash pain, pain due to cancer treatment, phantom limb pain, traumatic injury, complex regional pain syndrome and pain due to peripheral vascular disease.
The development of hyper-excited sensory nerve function has been described by Sollevi 1997 (1). These symptoms are often manifested as neuropathic pain. Neuropathic pain is a persistent, chronic pain usually described as a burning, shooting or lancinating sensation without an obvious cause. These symptoms are often associated with damage to nerves or nerve fibers. Such pain is associated with the transmission of abnormal pain signals from injured peripheral nerves to neurons in the brain and spinal cord. Briefly, the sensory nervous system projects signals to the central nervous system (CNS), mediating information from the periphery to the brain. These comprise signals from sensors in peripheral tissues and other organs, sensitive for qualities like touch, temperature changes, vibration, painful stimuli, pressure, vision, hearing, smell, taste and balance. This sensory nervous system is an important physiological control in the subject""s relation to the environment.
The sensory nervous system can be damaged by various types of trauma, such as infections and mechanical lesions including whip-lash injury, diseases such as diabetes and HIV infection, cancer or HIV treatments. This can result in disturbance in the signal transmission into the CNS, leading to reduced perception of sensory signals (hypoestesia) as well as hyper-function (more excited signals in the CNS) due to some largely unknown changes in the nerve transmission process (neuropathic damage). The neuropathic condition with hyper-excitation is described as a xe2x80x9cwind-upxe2x80x9d phenomenon and often involves several of the above mentioned sensory functions.
This may therefore be associated with decreased thresholds for touch and temperature (hyperesthesia), discomfort in the perception for touch and temperature (dysesthesia), discomfort or pain with touch, pressure and/or temperature stimulation (allodynia), and hypersensitivity to pain stimuli (hyperalgesia), balance disturbance, disturbance of auditory type (tinnitus) as well as ganglionic dysfunction. These types of hyper-reactive sensory nerves may develop after various types of trauma, and are called chronic when persistent for more than 3-6 months.
Adenosine, administered intravenously or intrathecally, has been proposed as a treatment for this sensory nerve hyper-reactivity (1, 2, 3). The objective of the treatment is to restore a normal perception of pain, as well as other sensory functions, in patients suffering from pathological hyper-excitation due to nerve damage.
Similarly adenosine has been proposed as treatment for other pain states derived from nociception including acute pain, tissue injury pain and nerve injury pain (15). Adenosine modulates the pain response by stimulating A1 adenosine receptors present in the dorsal root of the spinal cord and higher brain centers (spraspinal mechanisms) (14). A1 agonists have been shown to be effective treatment for every pain type in animal pain models (see Table 2 of, Yaksh, 1999, reference 15). However, A1 agonists also cause cardiovascular side effects and CNS side effects such as heart block, hypotension and sedation.
Adenosine is an endogenous nucleoside present in all cell types of the body. It is endogenously formed and released into the extracellular space under physiological and pathophysiological conditions characterized by an increased oxygen demand/supply ratio. This means that the formation of adenosine is accelerated in conditions with increased high energy phosphate degradation. The biological actions of adenosine are mediated through specific adenosine receptors located on the cell surface of various cell types, including nerves (4). The hyper-reactive nerves increase adenosine release due to an increase in metabolic activity.
A1 receptors are widely distributed in most species and mediate diverse biological effects. The following examples are intended to show the diversity of the presence of A1 receptors rather than a comprehensive listing of all such receptors. A1 receptors are particularly ubiquitous within the central nervous system (CNS), with high levels being expressed in the cerebral cortex, hippocampus, cerebellum, thalamus, brain stem, and spinal cord. Immuno-histochemical analysis using polyclonal antisera generated against rat and human A1 adenosine receptors has identified different labeling densities of individual cells and their processes in selected regions of the brain. A1 receptor mRNA is widely distributed in peripheral tissues such as the vas deferens, testis, white adipose tissue, stomach, spleen, pituitary, adrenal, heart, aorta, liver, eye, and bladder. Only very low levels of A1 receptors are thought to be present in lung, kidney, and small intestine.
The present invention relates to a class of compounds known as allosteric modulators or allosteric enhancers. Prior to the present invention and its parent (U.S. patent application Ser. No. 09/654,994), allosteric enhancers have only been described for the A1 adenosine receptor (5, 6, 7). No allosteric modulators had been proven effective in neuropathic pain models at any concentration. A1 the currently known enhancers are derivatives of the 2-amino-3-benzoylthiophenes first described by Bruns et al. (5). These benzoylthiophenes are not agonists at the endogenous A1 adenosine receptor (5, 6, 8). Structurally, all known agonists for the A1 adenosine receptor are derivatives of adenosine. The presence of an unmodified ribose ring is essential for agonist activity at the A1 adenosine receptor (9). Benzoylthiophenes are not agonists at the A1 adenosine receptor. Importantly, these compounds are antagonists at the A1 adenosine receptor (5, 6, 7, 8). At low concentrations, these benzoylthiophenes enhance the effect of agonists. At higher concentrations, these compounds act as antagonists. Therefore, the concentration range where these compounds can enhance the effects of agonists is limited (8).
Mechanistically, benzoylthiophenes appeared to enhance A1 adenosine receptor function by stabilizing the high affinity state of the receptor-G-protein complex (8, 10). This property is manifested as an increase in high affinity binding in radioligand binding reactions where an agonist radioligand is used to label the A1 adenosine receptor. An enhancer that increases agonist binding can do so by either accelerating the association of agonist and receptor, or by retarding the dissociation of the xe2x80x9creceptor-ligandxe2x80x9d complex. Kinetic studies have shown the benzoylthiophenes to retard the dissociation of the xe2x80x9creceptor-ligandxe2x80x9d complex. In contrast, an agonist, or an antagonist will both compete with the radioligand for the binding site and accelerate the dissociation of the xe2x80x9creceptor-ligandxe2x80x9d complex (8). Since the benzoylthiophenes only selectively retard the dissociation of the xe2x80x9creceptor-ligandxe2x80x9d complex when an agonist radioligand is used, the benzoylthiophenes must bind to a site different from the agonist recognition site. This putative site is termed the allosteric site, and presumably, compounds that bind to this site and enhance the agonist effect are termed xe2x80x9callosteric enhancersxe2x80x9d.
Another challenge is that that wide distribution of adenosine receptors offers both opportunities and drawbacks for therapeutic intervention. As an example, A1 adenosine receptors are found in the CNS, in heart and adipose tissue. Thus, agonists are capable of reducing free fatty acid levels in the blood through their interaction with adenosine A1 receptors on fat cells. This is a useful feature in non-insulin dependent diabetes mellitus. However, the concomitant bradycardia and drop in mean arterial pressure due to interference with cardiovascular adenosine receptors are to be considered as serious side effects.
In the U.S. patent application Ser. No. 09/654,994, Compound T62 is disclosed in the parent application as being a potent allosteric adenosine A1 receptor antagonist. However, as disclosed, Compound T62 is used in relatively low dosages and as such is most effective in the treatment of neuropathic pain.
An object of the present invention is to provide a therapeutically useful enhancer with improved potency as an enhancer, and preferably, without antagonist property. The present invention describes the discovery of a compound that meets these criteria.
The present invention relates to a composition and a method for the treatment of hyper-excited sensory nerve functions, e.g., neuropathia in human subjects. The treatment method comprises oral administration, topical administration, subcutaneous administration, intravenous administration, or intrathecal administration of an allosteric enhancer at the adenosine A1 receptor.
It is demonstrated that (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-chlorophenyl)methanone (Compound T62) normalized hyper-excited sensory nerve functions in a model of neuropathic pain in low dosage levels.
Surprisingly, it has been found that Compound T62 is well tolerated in animals at high dosages. At these higher dosages the allosteric enhancer effect of Compound T62 can be applied to treat other pain mechanisms as well as treating neuropathic pain with higher dosages. 
The method of treatment comprises enteral, dermal, parenteral or subcutaneous administration of an effective amount of Compound T62, an A1 allosteric enhancer, to the patient. Another object of the present invention is to provide a composition comprising an adenosine A1 allosteric enhancer for the manufacture of a medicament for alleviation or normalization of a pathologically hyper-excited sensory nerve function in a conscious human subject. The invention further relates to a pharmaceutical preparation for alleviation or normalization of a pathologically hyper-excited sensory nerve function in a conscious human subject, comprising a selected allosteric enhancer for the adenosine receptor in a pharmaceutically acceptable carrier.
Accordingly, the invention provides a method using an allosteric enhancer for the A1 adenosine receptor as a means to reduce or eliminate neuropathic symptoms in human subjects. An allosteric enhancer for the A1 receptor is preferably administered orally in a tablet, capsule, suspension or other suitable oral dose forms. More rapid pharmacologically effect may be elicited by parenteral administration. For parental administration, it may be administered in a central vein or preferably in a peripheral vein, by a bolus injection. If desired, an allosteric enhancer can also be given intrathecally.
When given orally, a dose range of 100 mg to 1000 mg (approximately 1 to 15 mg/kg free base per dose) can be given to a patient. Doses given parentally will be in the range of 0.01 to 1 mg/kg). This treatment can be individually repeated at regular intervals. The invention is a new principle for alleviation of hypersensitivity of the sensory nerve system e.g. such as the perception of touch, temperature, vibration, pain and pressure on the skin. The invention further applies to alleviation of hyperfunction of other functions, e.g. visual function, auditory function, olfactory function, taste, balance and ganglionic transmission.